Prostaglandins are found in virtually all tissues and glands and are extremely potent mediators of a diverse group of physiological processes (Funk, C. D. Science, 2001, 294, 1871-1875). Prostaglandins can participate in a wide range of body functions, such as the contraction and relaxation of smooth muscle (Andersson, K. E., Forman, A. Acta Pharmacol. Toxicol., 1978, 43 (Suppl. 2), 90-95), the dilation and constriction of blood vessels (Abramovich, D. R., Page, K. R., Parkin, A. M. L. Br. J. Pharmac., 1984, 81, 19-21), control of blood pressure (Anderson, R. J., Berl, T., McDonald, K. M., Schrier, R. W. Kidney International, 1976, 10, 205-215), and modulation of inflammation and immunity (Hata, A. N., Breyer, R. M. Pharmacol. Ther., 2004, 103(2), 147-166). In general, prostaglandins and related compounds are transported out of the cells that synthesize them and affect other target cells close to their site of formation, mainly by interacting with the target cell's prostaglandin receptors to stimulate or inhibit some target cell function. They also alter the activities of the cells in which they are synthesized. The nature of these effects may vary from one cell type to another, and from the target cell type.
Prostaglandin F2α ((Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((S,E)-3-hydroxyoct-1-enyl)cyclopentyl)hept-5-enoic acid) has the following structure:

Many prostaglandins are characterized by the substituents on the cyclopentyl ring. Prostaglandin F2α and its prostaglandin analogs in general possess two hydroxyl groups on the cyclopentyl ring in a cis configuration relative to each other, and two hydrocarbon side chains (α and ω side chains) on the cyclopentyl ring in a trans configuration relative to each other. Prostaglandin F2α analogs can have a varying number of carbon-carbon double bonds in the hydrocarbon side chains, and side chain substituents may vary. In addition, for PGF2α analogs, the α side chain may terminate with a carboxylic acid moiety (free acid form), a carboxylic ester moiety, or a carboxamide moiety. The ester and amide forms of PGF2α analogs may be used as prodrugs in the treatment of prostaglandin F receptor (FP receptor)-mediated conditions or processes.
Prostaglandin F2α (PGF2α) is an endogenous ligand of the Prostaglandin F receptor (FP receptor) that exerts its receptor-mediated physiological activities with EC50s in the nanomolar concentration range. The FP receptor is widely distributed in many species (Speroff, L., Ramwell, P. W., Am. J. Obstet. Gynecol., 1970, 107, 1111-1130; Samuelsson, B., Goldyne, M., Granstrom, E., et al., Ann. Rev. Biochem., 1978, 47, 997-1029).
Intravenous, intracameral, and topical administrations of PGF2α, have been shown to cause prolonged reduction of intraocular pressure (IOP), a common symptom of glaucoma (Camras, C. B., Bito, L. Z., Eakins, K. E., Invest. Ophthamol. Vis. Sci., 1977, 16(12), 1125-1134; Giuffrè, G., Graefe's Arch. Clin. Exp. Ophthalmol., 1985, 222, 139-141).
Synthetic and relatively metabolically stable analogs of PGF2α having therapeutic use include latanoprost, bimatoprost, fluprostenol, and cloprostenol. The PGF2α analog latanoprost free acid is potent FP receptor agonist with an EC50 value of 3.6 nM (Stjernschantz, J., Resul, B., Drugs of the Future, 1992, 17 691-704). Latanoprost isopropyl ester, generally known as latanoprost (IUPAC name isopropyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]-cyclopentyl]hept-5-enoate, common name 17-phenyl-13,14-dihydro trinor Prostaglandin F2α isopropyl ester, trade name Xalatan®), is a prodrug of latanoprost free acid and is used in ophthalmic formulations for the reduction of IOP associated with open angle glaucoma and ocular hypertension (Camras, C. B., Schumer, R. A., Marsk, A., at al., Arch. Ophthalmol., 1992, 110, 1733-1738; Camras, C. B., Alm, A., Watson, P., Stjernschantz, J., Ophthalmology, 1996, 103, 1916-1924). Additionally, a single instillation of topical latanoprost has shown to at least temporarily increase blood flow in the optical nerve head (ONH) of subjects with glaucoma (Tamaki, Y., Nagahara, N., Araie, M., et al., J. Ocular Pharm. Ther., 2001, 17(5), 403-411). Topical latanoprost administration also modulates processes such as hair growth (Johnstone, M., Am. J. Ophthalmol., 1997, 124, 544-547). Long-term topical use of latanoprost has been associated with iridial pigmentation and eyelash elongation (Chiba, T., Kashiwagi, K., Ishijima, K., at al., Jpn. J. Ophthalmol., 2004, 48, 141-147)

Other metabolically stable synthetic analogs of PGF2α have been discovered and developed as treatments for a variety of conditions. Bimatoprost (IUPAC name (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxy-5-phenylpent-1-enyl]cyclopentyl]-N-ethylhept-5-enamide, common name 17-phenyl trinor Prostaglandin F2α ethyl amide, trade name Lumigan®) is an N-ethyl amide prodrug of its free acid, which is a potent FP receptor agonist (Balapure, A. K., Rexroad, C. E., Kawada, K., at al., Biochem. Pharmacol., 1989, 38, 2375-2381; Lake, S., Gullberg, H., Wahlqvist, J., et al., FEBS Lett., 1994, 355, 317-325). Bimatoprost is approved for treatment of glaucoma-associated IOP (Woodward, D. F., Krauss, A. H., Chen, J., at al., Survey of Ophthalmology, 2001, 45, S337-S345) and has also been reported to enhance eyelash growth (Tosti, A., Pazzaglia, M., Voudouris, S., Tosti, G., Journal of the American Academy of Dermatology, 2004, 51, S149-S150).

The free acid fluprostenol is another synthetic PGF2α analog that is a potent FP receptor agonist (Abramovitz, M., Adam, M., Boie, Y., et al., Biochim. Biophys. Acta, 2000, 1483, 285-293). Fluprostenol isopropyl ester (trade name Travoprost®) is a prodrug form of (+)-fluprostenol and is approved for treatment of glaucoma-associated IOP (Sorbera, L. A., Castañer, J., Drugs of the Future, 2000, 25, 41-45). Like prodrugs of other FP receptor agonists such as latanoprost and bimatoprost, Travoprost® has been shown to enhance eyelash growth (Eisenberg, D., Toris, C., Camras, C., Survey of Ophthalmology, 2002, 47, S105-S115).

Cloprostenol (free acid) also possesses FP receptor agonist activity. Cloprostenol and cloprostenol analogs are useful for treating glaucoma and ocular hypertension (U.S. Pat. No. 6,723,748) and may also be useful in promoting pigmentation and eyelash growth.

Procedures describing the synthesis of PGF2α analogs have been disclosed (WO 93/00329; EP 0 364 417 B1; European Patent No. EP 0 544 899 B1; U.S. Pat. No. 7,498,458). WO 93/00329 (and subsequently granted European Patent No. EP 0 544 899 B1) describes a preparation of latanoprost esters from (−)-Corey lactone para-phenylbenzoate (PPB) alcohol, or (3aR,4S,5R,6aS)-4-(hydroxymethyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl biphenyl-4-carboxylate, in eight steps, namely:                1. Moffatt oxidation of the (−)-Corey lactone PPB alcohol to form the corresponding aldehyde:        
                2. Wittig reaction of the aldehyde with triphenyl-2-oxo-4-phenylbutylphosphonium iodide to form the enone intermediate shown below:        
                3. Stereoselective reduction of the enone provides an alcohol mixture comprising 15S-alcohol (3a) and 15R-alcohol (Epi-3a) with some enrichment in (3a) as shown below:        

It may be noted here that U.S. Pat. No. 6,689,901 describes a general procedure, and similar specific embodiments, that utilize (−)-B-chlorodiisopinocampheylborane ((−)-DPC) as the reducing agent in the enone reduction step.                4. Hydrogenation to reduce the carbon-carbon double bond completes the framework of the latanoprost ω-chain as shown below:        
                5-6. Lactone reduction and subsequent deprotection provide the lactol as shown below:        
                7. A subsequent Wittig reaction with 4-carboxybutyl-triphenylphosphonium bromide provides latanoprost free acid:        
                8. Esterification of latanoprost free acid with the desired alcohol ROH affords the corresponding latanoprost ester as described below:        

The latanoprost ester synthetic process described in WO 93/00329 suffers from a low overall yield at both the gram and kilogram scale. Loss of valuable material arises from difficulties in purifying intermediates. Purification of the 15S/R-alcohol mixture produced in the enone reduction step to isolate the sufficiently stereopure 15S-alcohol (3a), for example, employs both column chromatography and recrystallization and affords yields of 35% (200 g of starting ketone) and 38% (19.3 kg of starting ketone).
An alternative process is described (Resul, B., Stjernschantz, J., No, K., et al., J. Med. Chem., 1993, 36, 243-248) in which the first Wittig procedure is replaced with the Wadsworth-Emmons method to provide the ketone intermediate with only a small increase in yield. The most significant difference from the above-described process, however, is the removal of the PPB protecting group before lactone reduction, which gives yields essentially equivalent with those of WO 93/00329 over the two steps. Overall, this method provides no significant advantage over that of WO 93/00329. U.S. Pat. No. 7,268,239 discloses a process whereby, in one embodiment, latanoprost is synthesized in eleven linear steps from a protected Corey lactone compound of the following formula:
The process comprises the following steps:                1. The benzoyl-protected Corey lactone alcohol is oxidized to the corresponding aldehyde by subjection to a catalytic amount of a stable organic nitroxyl radical as illustrated below:        
                2. The aldehyde is reacted with a phosphonate ester to provide the ketone intermediate as a white solid with 77% yield from the starting material of step 1 as shown below:        
                3. The ketone is stereoselectively reduced with borane-dimethylsulfide complex in the presence of a catalytic amount of (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole (‘Corey catalyst’) to give a mixture of alcohol epimers enriched with the (S)-hydroxy epimer as a crude oil. A purification that comprises a crystallization step and a tedious chromatography step afford the desired isomer as a white solid with 65% yield as shown below:        
                4. The benzoyl protecting group is removed to provide the diol intermediate as an oil with 99.1% yield as shown below:        
                5. The α,β-unsaturated alcohol is subsequently hydrogenated to provide the saturated diol intermediate analog as an oil with 94.8% yield as illustrated below:        
                6. The diol is reacted with about two molar equivalents of triethylchlorosilane to provide the bis-triethylsilyl-protected intermediate as an oil with 97.6% yield as shown below:        
                7. The lactone is subsequently reduced to provide the lactol as an oil with 97.3% yield:        
                8. A Wittig reaction involving the lactol intermediate and (4-carboxybutyl)-triphenylphosphonium bromide provides the regioisomeric mixture of bis-triethylsilyl protected triol acids as a crude oil as depicted below:        

The crude oil product generally includes a mixture of both the cis and trans forms of the bis-silylated free acid intermediates. The trans forms are typically removed from the mixture by chromatography.                9. The regioisomeric mixture of carboxylic acids is esterified with 2-iodopropane to provide the corresponding mixture of isopropyl esters as an oil as shown below:        
                10. The ester mixture is reacted with triethylchlorosilane to provide a single tris-triethylsilyl-protected triol isopropyl ester as an oil with approximately 79% yield over three steps from the bis-triethylsilyl protected diol lactone intermediate as illustrated below:        
                11. The tris-triethylsilylated intermediate is deprotected with a catalytic amount of pyridinium-p-toluenesulfonate and the product is subsequently purified by preparative HPLC to provide latanoprost as an oil with an 18.7% yield over the eleven steps:        

The process from U.S. Pat. No. 7,268,239 described above involves both a crystallization and silica chromatography in step 3 to separate the epimers formed in the reduction reaction. The disclosure presents a medium pressure liquid chromatography (MPLC) method that can purify multiple injections of impure product without having to repack the column, a method that minimizes quantities of both stationary phase and eluent deployed to carry out product purification versus the traditional method of running a single injection through a packed silica column.
In view of the problems associated with prior art processes, it is highly desirable to provide an alternative process for the synthesis of latanoprost and related PGF2α analogs and salts thereof. It is also highly desirable to provide synthetic intermediates that can be purified with greater ease and efficiency.